The anti-neurodegeneration drug clioquinol inhibits the aging-associated protein CLK-1.
The development of neurodegenerative diseases such as Alzheimer, Parkinson, and Huntington disease is strongly age-dependent. Discovering drugs that act on the high rate of aging in older individuals could be a means of combating these diseases. Reduction of the activity of the mitochondrial enzyme CLK-1 (also known as COQ7) slows down aging in Caenorhabditis elegans and in mice. Clioquinol is a metal chelator that has beneficial effects in several cellular and animal models of neurodegenerative diseases as well as on Alzheimer disease patients. Here we show that clioquinol inhibits the activity of mammalian CLK-1 in cultured cells, an inhibition that can be blocked by iron or cobalt cations, suggesting that chelation is involved in the mechanism of action of clioquinol on CLK-1. We also show that treatment of nematodes and mice with clioquinol mimics a variety of phenotypes produced by mutational reduction of CLK-1 activity in these organisms. These results suggest that the surprising action of clioquinol on several age-dependent neurodegenerative diseases with distinct etiologies might result from a slowing down of the aging process through action of the drug on CLK-1. Our findings support the hypothesis that pharmacologically targeting aging-associated proteins could help relieve age-dependent diseases.
Wang
Ying
Y
Department of Biology, McGill University, Montráal, Quábec H3A 1B1, Canada and Chronogen Inc., Montráal, Quábec H1W 4A4, Canada.
Branicky
Robyn
R
Department of Biology, McGill University, Montráal, Quábec H3A 1B1, Canada and Chronogen Inc., Montráal, Quábec H1W 4A4, Canada.
Stepanyan
Zaruhi
Z
Department of Biology, McGill University, Montráal, Quábec H3A 1B1, Canada and Chronogen Inc., Montráal, Quábec H1W 4A4, Canada.
Carroll
Melissa
M
Department of Biology, McGill University, Montráal, Quábec H3A 1B1, Canada and Chronogen Inc., Montráal, Quábec H1W 4A4, Canada.
Guimond
Marie-Pierre
MP
Department of Biology, McGill University, Montráal, Quábec H3A 1B1, Canada and Chronogen Inc., Montráal, Quábec H1W 4A4, Canada.
Hihi
Abdelmadjid
A
Department of Biology, McGill University, Montráal, Quábec H3A 1B1, Canada and Chronogen Inc., Montráal, Quábec H1W 4A4, Canada.
Hayes
Steve
S
Department of Biology, McGill University, Montráal, Quábec H3A 1B1, Canada and Chronogen Inc., Montráal, Quábec H1W 4A4, Canada.
McBride
Kevin
K
Department of Biology, McGill University, Montráal, Quábec H3A 1B1, Canada and Chronogen Inc., Montráal, Quábec H1W 4A4, Canada. Electronic address: kevinmcbride@sympatico.ca.
Hekimi
Siegfried
S
Department of Biology, McGill University, Montráal, Quábec H3A 1B1, Canada and Chronogen Inc., Montráal, Quábec H1W 4A4, Canada. Electronic address: Siegfried.Hekimi@McGill.Ca.
D000375:Aging / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007464:Clioquinol / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006899:Mixed Function Oxygenases; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism
C104339:CLK-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D002614:Chelating Agents; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D007464:Clioquinol; D006899:Mixed Function Oxygenases; C434481:Coq7 protein, mouse